HU198302B - Process for producing new platine-komplexes and citostatice pharmaceuticalcompositions containing them as active components - Google Patents

Abstract

A diamine platinum (II) complex represented by the general formula [wherein R₁, R₂, R₃ and R₄ are each a hydrogen atom or a lower alkyl group; and two X's are each a halogen atom or jointly form a group represented by (wherein R₅ and R₆ are each a hydrogen atom or a lower alkyl group) or a group represented by (wherein m is l or 2)] is useful as an anti-tumour agent.

Description

The present invention relates to novel platinum complexes having antitumor activity and to pharmaceutical compositions containing these compounds as active ingredients.

Of the platinum complexes having antitumor activity, cis-platinum (d-dichlorodiamine-platinum) is already commercially available and is used in many cases because of its potent activity. Other platinum complexes with other antitumor activity are known in the literature. Among the above compounds, the platinum complexes containing straight chain alkyl diamine as the ligand are limited to compounds containing a compound of formula (I) as a ligand. In the formula (1), R is hydrogen or a substituent such as alkyl, hydroxy or the like, and n is an integer from 1 to 3 (Japanese Patent Laid-Open Publication Nos. 15416/1982 or 103192/1981).

As mentioned above, cis-platinum is commercially available as an anti-cancer platinum complex. However, cis-platinum has a very high renal toxicity, which is a dose-limiting factor. Thus, when using ds-platinum, it is required that large amounts of water be administered to the patient before and during administration, and that cis-platin be used with a diuretic over a long period of time. In addition, since cis-platinum is only slightly and slowly soluble in water, it can only be administered in very low concentration concentrates. Furthermore, the emetic effect of ds-platinum is very potent, which is also a problem during treatment. Because of the above-mentioned disadvantageous properties of cis-platin, research has focused on platinum complexes which are more water soluble, have lower renal toxicity, and have less emetic activity than cis-platinum. However, to date, such research has not been successful.

When 1,4-butanediamine or a derivative thereof reacts with a platinum atom to form a coordinate compound through the two nitrogen atoms of the diamine, including the platinum atom, a ring structure of 7 atoms is formed, which is also shown below in formula (11). Generally, the preparation of seven-membered ring structures is very difficult in the conventional manner. As a result of extensive research, we have been able to prepare platinum (II) complexes containing 1,4-butanediamine or a derivative thereof as a ligand and found that these complexes have antitumor activity and significantly less renal toxicity than dsplatin. The invention is based on the above recognition.

More particularly, the present invention relates to the preparation of diamine-platinum (II) complexes of formula (11). In the general formula (11)

R 1, R ₂ , R 1 and R 4 are hydrogen or lower alkyl, the two X are halogen, or together a group of formula (a) or (b) - wherein R 1 and R 1 are hydrogen or lower alkyl or of formula (c) or (d) wherein m is 1 or 2.

In the above general formula (11), R ₁ , R ₂ , R ₃ , R 4, R 1 and R 6 are defined as lower alkyl having from 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl and isopropyl.

The halogen atom represented by X in formula (11) is, for example, chlorine, bromine, etc. means.

Preferred compounds of formula (11) are those wherein the two X together form a group of formula (b) or (c). Other preferred compounds are those which are R, and R ₂ is H (11) wherein.

Representative compounds of formula II include, but are not limited to:

Dsz [dichloro-1,4-butanediamine-platinum],

2. ds- [cyclobutane-1,1-dicarboxylate, 4-butanediamine-platinum],

3. dis- (4-oxadeclohexane-1,1-dicarboxylato-1,4-butanediamine-platinum),

4. di- [dichloro-1-methyl-1,4-butanediamine platinum,

5. ds- [dichloro-1-methyl-1,4-butanediamine-platinum],

6. di- [malonate-1-methyl-1,4-beta-diamine-platinum],

7. ds- [dclobutane-1,1-dicarboxylato-1-methyl-1,4-butanediamine-platinum],

8. ds - [(dimethyl malonate) -1-methyl-1,4-butanediamine platinum],

9. ds - [(ethyl malonate) -1-methyl-1,4-butanediamine-platinum],

Dsz [dichloro-1-ethyl-1,4-butanediamine-platinum],

11. Ris [cyclobutane-1,1-dicarboxylato-1-ethyl-1,4-butanediamine-platinum],

12. dis- [4-oxa-cyclohexane-1,1-dicarboxylato-1-ethyl-1,4-butanediamine-platinum],

13. di- [dichloromethane-2-methyl-1,4-butanediamine-platinum],

14. cis [malonate-2-methyl-1,4-butanediamine-platinum],

15. cis-diclobutane-1,1-dicarboxylato-2-methyl-1,4-butanediamine-platinum],

16. dis [4-oxadeclohexane-1,1-dicarboxylato-2-methyl-1,4-butanediamine-platinum],

17. cis - [(dimethyl malonate) -2-methyl-1,4-butanediamine platinum],

18-di- [ethyl malonate] -2-1,4-butanediamine-platinum],

Ds [dichloro-2,2-dimethyl-1,4-butanediamine-platinum],

Ds- [oxalato-2,2-dimethyl-1,4-butanediamine-platinum],

21. ds- [malonate-2,2-dimethyl-1,4-butanediamine-platinum],

22. di- [dclobutane-1,1-dicarboxylato-2,2-dimethyl-1,4-butanediamine-platinum),

23. dis [4-oxaddohohexane-1,1-dicarboxylato-2,2-dimethyl-1,4-butanediamine-platinum],

Ds - [(dimethyl malonate) -2,2-dimethyl-1,4-butanediamine platinum],

25. ds- [dichloro-1,1-dimethyl-1,4-butanediamine-platinum],

26. di- [oxalato-1,1-dimethyl-1,4-butanediamine-platinum],

27. ds- [cyclobutane-1,1-dicarboxylate-1,1-dimethyl-1,4-butanediamine-platinum],

28. ds - [(dimethyl malonate) -1,1-dimethyl-1,4-butanediamine platinum],

29. ds- [dichloro-2-ethyl-1,4-butanediamine-platinum],

30. Ris-oxalate-2-ethyl-1,4-butanediamine-platinum],

31 d- [malonate-2-ethyl-1,4-butanediamine-platinum],

32 ds- [cyclobutane-1,1-dicarboxylate-2-ethyl-1,4-butane-diamine-platinum],

33. dis - [(dimethyl malonate) -2-ethyl-1,4-butanediamine platinum].

34. di- [oxalato-2-isopropyl-1,4-butanediamine-platinum],

35-dichloro-1,2-dimethyl-1,4-butanediamine-platinum].

Compounds of formula (11) may be prepared using known procedures such as those described in Indian J. Chem., 8, 193 (1970), but the process must be modified.

According to the present invention, compounds of formula (11) are prepared by reacting a diamine of formula (V):

R 1, R ₂ , R ₃ and R 1 are as defined above, with a compound of formula IV, wherein M is a monovalent cation atom and Hal is halogen, and the reaction product is a dihalogen of formula 11a. -diamine-platinum complex, wherein R 1, R-2, R 31 R 4 and Hal are as defined above, and then, if desired, reacting the resulting compound with silver ions in the presence of water to form a diacvo complex with a (Via) With dicarboxylic acid of formula (VIb), (VIIIc) or (Vld), wherein R 1, R ₆ and m are as defined above, or a salt thereof.

The process of the invention will be described in detail below.

The compound of formula (IV) is represented by the formula (1). Reaction Scheme I with a diamine of formula (V). In the formulas of the reaction scheme, a monovalent cation atom as defined for M is, for example, sodium, potassium, cesium or the like, Hal is a halogen such as chlorine, bromine or iodine, and R 1, R ₂ , R ₃ and R 4 has the meaning given above.

In the above reactor, the tetrahalodoplatinate and the diamine are reacted in an aqueous medium, preferably water, to give the dihalododiamine platinum. The water is preferably used in an amount of from 5 to 500 liters, preferably from 5 to 160 liters, most preferably from 20 to 80 liters, per mole of tetrahaloplatinate. The diamine is preferably used in an amount of 0.5 to 4 moles, preferably 0.9 to 1.2 moles, per mole of tetrahaloplatinate. The reaction is carried out at 0 to 100 ° C, preferably 50 to 70 ° C, with stirring. The reaction is preferably carried out by gradually adding the aqueous solution of tetrahaloplatinate and the aqueous solution of diamine separately into distilled water. The addition is preferably carried out slowly, usually for 1 to 6 hours. The reaction may be carried out in air, but is preferably carried out in an inert gas atmosphere, such as a nitrogen atmosphere.

In the next step, the dihalodiamine platinumate of formula (11a) is suspended in water and reacted with silver ions according to Scheme 2. The resulting silver halide precipitate was removed by filtration to give an aqueous solution of the diaco complex (111).

Suitable amounts of water, preferably 5 to 150 liters, of water per mole of compound (Ha) are used to suspend the dihalodiamine complex of formula (11a). The amount of silver ion is not critical, but economically it is preferable to use 0.5 to 6 equivalents of silver ion per 1 equivalent of the dihalodiamine complex of formula (11a). 1.9-2 equivalents of silver ion are particularly preferred to avoid excess administration. 11a. The reaction is carried out at 0 to 100 ° C, preferably 60 to 80 ° C, with stirring. The silver ion is added, for example, in the form of silver nitrate, silver sulfate, silver perchlorate or silver acetate.

The resulting diaco complex (III) is finally reacted with a dicarboxylic acid salt, a dicarboxylic acid monohydrogen salt or dicarboxylic acid. The reaction is carried out, for example, by adding to the aqueous solution of the diaco complex of the general formula (HI) an aqueous solution containing an appropriate amount of a dicarboxylic acid salt, a dicarboxylic acid monohydrogen salt or a dicarboxylic acid. The above salt or acid is preferably used in an amount of 0.5 to 10 moles, more preferably 0.9 to 6 moles, relative to 1 mole of the diacvo complex III. The reaction is carried out at a temperature of 0 to 100 ° C, preferably 40 to 90 ° C. The reaction product is a compound of formula (11b) wherein X 'is a group other than a halogen atom as defined for X.

The structure of the compounds of formula (11) obtained by the process of the present invention was determined by various analytical methods such as elemental analysis, infrared absorption spectrometry, fast atom bombardment mass spectrometry (FABMS Pt ¹⁹⁴ ) and the like.

The compounds of the present invention have very low renal toxicity and emetic activity, are well solubilized in water and rapidly dissolve in water, have excellent antitumor activity, and are therefore useful as pharmaceutical compositions for treating tumors. They may be used for the treatment of tumors in the form of injectable or oral formulations and other forms. In addition, the compounds of the invention are stable in air at room temperature and do not require low temperature storage.

The invention is further illustrated by the following non-limiting examples.

Example 1 Preparation of di- [Dichloro-1,4-butanediamine platinum] (Compound 1) Potassium tetrachloroplatinate (II) g is dissolved in 350 ml of water. A solution of potassium iodide (16 g) in water (50 ml) was added with stirring. The reaction mixture was further stirred for 5 minutes at 35 ° C to give a black aqueous solution of potassium [tetraiododoplatinate (U)].

In another flask, 2.12 L of 1,4-butanediamine was dissolved in 400 mL of water to give an aqueous solution of 1,4-butanediamine.

Weigh 250 ml of water into a flask. To the water was added dropwise the aqueous potassium [tet-31-rhododoplatinate (II)] solution and the aqueous 1,4-butanediamine solution simultaneously for two hours at a constant rate while the mixture was heated to 60 ° C. The resulting reddish-brown crystals were filtered and washed with water, ethanol and diethyl ether, respectively. The crystals were dried in vacuo. 9.74 g (75.3%) of di- [diiodo-1,4-butanediamine platinum] are obtained in crystalline form.

g of the compound obtained above is suspended in 20 ml of water. To the suspension was added a solution of 620 mg of silver nitrate in 10 ml of water. The mixture was stirred at 60 ° C for 20 minutes. The reaction mixture was then cooled to room temperature and the silver iodide was removed by filtration. The silver iodide precipitate was washed with water. The filtrate and the washings were combined and a solution of 653 mg of sodium chloride in 5 ml of water was added. The mixture was stirred at room temperature for 10 minutes. The resulting yellow crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

Yield: 538 mg.

Found: C, 13.44; H, 3.56; N, 8.04 Found: C, 13.57; H, 3.42; N, 7.91; Pt, 55.09. Pt: 54.8%.

FAB-MS: (M + H) ⁺ = 353.

Example 2 Preparation of ds- [Cyclobutane-1,1-dicarboxylato-1,4-butanediamine-platinum] (Compound 2)

The same procedure as in Example 1 was used, but instead of a solution of 653 mg of sodium chloride in 5 ml of water, a solution of 537 mg of 1,1-dclobutanedicarboxylic acid in 7.26 ml of 1 N sodium hydroxide was used. The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was then concentrated to 5 ml and cooled to 0 ° C. The precipitated white crystals were strained, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

457 mg of the title compound are obtained.

Elemental analysis results: calculated. C, 28.24; H, 4.27; N, 6.59; Pt: 4S, 86%. Found: C, 28.56; H, 4.41; N, 6.48; Pt: 45.2 %.

FAB-MS: (M + H) ⁺ = 425.

Example 3 Preparation of di- [4-Oxa-dichlohexane-1,1-dicarboxylato-1,4-butanediamine-platinum] (Compound 3)

The procedure described in Example 1 was followed, but instead of a solution of sodium chloride (653 mg) in water (5 ml), a solution of 4-oxadclohexane-1,1-dicarboxylic acid (324 mg) in 1N aqueous sodium hydroxide solution (7.26 ml) was used. After addition of the above solution, the reaction mixture was stirred for 2 hours at 60 ° C. The reaction mixture was concentrated to 5 mL and cooled to 0 ° C. The precipitated white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

493 mg of the title compound are obtained.

Found: C, 28.76; H, 4.62; N, 6.04 Found: C, 29.01; H, 4.43; N, 6.15; Pt, 42.82. Pt: 42.4%.

FAB-MS: (M + H) ⁺ = 455.

Example 4 \

Preparation of ds- [Dichloro-1-methyl-1,4-butahydiamine-platinum] (Compound 4)

The procedure described in Example 1 was followed, but 2.12 g

Instead of 1,4-butanediamine, 2.46 g of 1-methyl-1,4-butanediamine was used. 9.64 g (72.6%) of di- [diiodo-1-methyl-1,4-butanediamine platinum] are obtained in the form of reddish-brown crystals. In the following, the procedure of Example 1 was followed except that 1 g of the above compound, 604 mg of sodium nitrate and 636 mg of sodium chloride were used.

400 mg of the title compound are obtained in yellow crystalline form.

Found: C, 16.57; H, 3.98; N, 7.81. Found: C, 16.31; H, 3.83; N, 7.61; Pt, 52.99. Pt: 53.0%.

FAB-MS. (M + H) ⁺ = 367.

Example 5 Preparation of ds [Odalato-1-methyl-1,4-butanediamine platinum] (compound 5)

Following the procedure of Example 4, but adding a solution of 669 mg of potassium oxalate monohydrate in 5 ml of water instead of 636 mg of sodium chloride, the reaction mixture is stirred at 60 ° C for 2 hours. The resulting mixture was then concentrated to 5 mL and cooled to 0 ° C. The precipitated white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

426 mg of the title compound 5 are obtained.

Found: C, 22.01; H, 3.71; N, 6.98. Found: C, 21.82; H, 3.66; N, 7.27; Pt, 50.63. Pt: 52.0%.

FAB MS (MH ⁺ ) = 385.

Example 6 Preparation of ds [Malonato-1-methyl-1,4-butane-dlaminoplatinum] (compound 6)

The procedure is as in Example 4, but using a solution of 378 mg of malonic acid in 6.90 ml of 1 N aqueous sodium hydroxide solution instead of 636 mg of sodium chloride in 5 ml of water. After the addition of the above solution, the resulting mixture was stirred at 50 ° C for 8 hours. The reaction mixture was then concentrated to 5 ml and washed with water at 0 ° C, then with ethanol and dried in vacuo.

305 mg of the title compound 6 are obtained.

Found: C, 24.38; H, 4.27; N, 6.80 Found: C, 24.06; H, 4.04; N, 7.02; Pt, 48.85. Pt: 48.4%.

FAB-MS: (M + H) < + > = 399.

Example 7 Preparation of ds- [Cyclobutane-1,1-dicarboxylato-1-methyl-1,4-butanediamn-platinum] (Compound 7)

The procedure described in Example 4 is followed, but using a solution of dclobutane-1,1-dicarboxylic acid (523 mg) in 1N aqueous sodium hydroxide solution (52.08 mg) instead of a solution of sodium chloride (636 mg) in 5 ml of water. The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated to 5 ml and cooled to 0. The precipitated white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

608 mg of the title compound 7 are obtained.

Found: C, 29.88; H, 4.44; N, 6.53. Found: C, 29.08; H, 4.59; N, 6.38; Pt, 4.40. Pt: 44.1%.

FAB-MS; (M + H) ⁺ = 439.

Example 8 Preparation of dsi - [(dimethyl malonate) -1-methyl-1,4-butanediamine platinum] (compound 8)

The procedure is as in Example 4, but using a solution of 480 mg of dimethylmalonic acid in 7.08 ml of 1 N aqueous sodium hydroxide solution instead of 636 mg of sodium chloride in 5 ml of water. After adding the above solution, the reaction mixture was stirred at 50 ° C for 6 hours. The mixture was concentrated to 5 mL and then cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water and then with ethanol and dried in vacuo.

532 mg of the title compound 8 are obtained.

Elemental analysis: Calculated: C; 28.11, H 4.72, N 6.55, Pt 45.65. Found: C 28.40, H 4.91, N 6.30, Pt 46.4%.

FAB-MS: (M + H) ⁺ = 427.

Example 9

Preparation of Cis - [(Ethyl malonate) -1-methyl-1,4-butanediamine platinum] (Preparation of compound 9)

The procedure is as in Example 4, but using a solution of 480 mg of ethyl malonic acid in 7.08 ml of 1 N aqueous sodium hydroxide solution instead of 636 mg of sodium chloride in 5 ml of water. The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated to 5 mL and then cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little 0 V water, then with ethanol and dried in vacuo.

575 mg of the title compound 9 are obtained.

Found: C, 27.88; H, 4.65; N, 6.48. Found: C, 28.11; H, 4.72; N, 6.55; Pt, 45.65. Pt: 46.1%.

FAB-MS: (M + H) < + > = 427.

Example 10 - Preparation of dsi [dichloro-1-ethyl-1,4-butanediamine-platinum] (compound 10)

The procedure described in Example 1 was followed, but 2.12 g

Instead of 1,4-butanediamine, 2.80 g of 1-ethyl-1,4-b post-dianthine was used. 10.90 g (80.1%) of di- [diiodo-1-ethyl-1,4-butanediamine platinum oil are obtained in the form of red banana crystals. In the following, the procedure of Example 1 was followed except that 1 g of the above compound, 589 mg of silver nitrate and 620 mg of sodium chloride were used.

394 mg of the title compound 10 are obtained in the form of yellow crystals.

Found: C, 18.99; H, 4.50; N, 7.55. Found: C, 18.86; H, 4.22; N, 7.33; Pt, 51.04. Pt: 50.1%. .

FAB-MS: (M + H) ⁺ = 381.

Example 11 Preparation of ds [Gclobutane-1,1-dicarboxylato-1-ethyl-1,4-butanediamine platinum] (Compound 11)

The procedure described in Example 10 was followed, but instead of a solution of 620 mg of sodium chloride in 5 ml of 5 ml of water, a solution of 510 mg of dclobutanedicarboxylic acid in 6.90 ml of 1 N aqueous sodium hydroxide was used. After addition of the above solution, the reaction mixture was stirred at 60 ° C for 2 hours, then concentrated to 5 ml and cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

342 mg of the title compound 11 are obtained.

Found: C, 31.53; H, 4.71; N, 6.36. Found: C, 31.79; H, 4.89; N, 6.18; Pt, 43.03. Pt: 42.6%.

FAB-MS: (M * H) ⁺ = 453.

Example 12 Preparation of di- [4-Oxa-dclohexane-1,1-dicarboxylato-1-ethyl-1,4-butanediamine-platinum] (Compound 12)

The procedure described in Example 10 was followed, but instead of a solution of 620 mg of sodium chloride in 5 ml of water, a solution of 616 mg of 4-oxadclohexane-1,1-dicarboxylic acid in 7.08 ml of 1 N aqueous sodium hydroxide was used. The reaction mixture obtained by adding the above solution was stirred at 60 ° C for 2 hours, then concentrated to 5 ml and cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water and then with ethanol, and dried in vacuo.

321 mg of the title compound 12 are obtained.

Found: C, 32.51; H, 5.12; N, 6.01 Found: C, 32.30; H, 5.00; N, 5.79; Pt: 40.35. Pt: 39.2%.

FAB-MS: (M + H) ⁺ = 483.

Example 13.

Preparation of ds- [Dichloro-2-methyl-1,4-butanediamine-platinum] (compound 13)

The procedure described in Example 1 was followed, but 2.12 g

2.46 g of 2-methyl-1,4-butanediamine are used instead of 1,4-butanediamine. 9.94 g (74.9%) of di- [diiodo-2-methyl-1,4-butanediamine platinum] are obtained in the form of tan crystals. In the following, the procedure described in Example 1 was followed except that 1 g of the above compound, 604 mg of silver nitrate and 636 mg of sodium chloride were used.

238 mg of the title compound 13 are obtained in the form of yellow crystals.

Hemanalysis results:

Found: C, 16.31; H, 3.83; N, 7.61; Pt, 52.99; Found: C, 16.15; H, 3.70; N, 7.44; Pt: 53. 1%.

FAB-MS: (M + H) ⁺ = 367.

Example 14 Preparation of ds [Malonato-2-methyl-1,4-butanediamine-platinum] (Compound 14)

The procedure is as in Example 13, but using a solution of 227 mg of malonic acid in 4.36 ml of 1 N aqueous sodium hydroxide solution instead of 636 mg of sodium chloride in 5 ml of water. The reaction solution obtained by adding the above solution was stirred at 60 ° C for 2 hours, then concentrated to 5 ml and cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water cooled to 0 ° C, then ethanol and dried in vacuo.

125 mg of dm are obtained.

Found: C, 24.22; H, 3.99; N, 7.41. Found: C, 24.06; H, 4.04; N, 7.02; Pt, 48.85. Pt: 49.4%.

FAB-MS: (M ₊ H) ⁺ = 399.

Example 15 Preparation of ds [Cyclobutane-1,1-dicarboxylato-2-methyl-1,4-butanediamine-platinum] (Compound 15)

The procedure described in Example 14 was followed, except that instead of a solution of 227 mg of malonic acid in 4.36 ml of 1N aqueous sodium hydroxide, 523 mg of dclobutane-1,1-dicarboxylic acid were added 7.29 ml of 1N aqueous sodium hydroxide. solution.

131 mg of the title compound are obtained in the form of white crystals.

Found: C, 30.20; H, 4.31; N, 6.15 Found: C, 30.07; H, 4.59; N, 5.38; Pt, 44.40. Pt: 44.5%.

FAB-MS: (M + H) ⁺ = 439.

Example 16 Preparation of di- [4-Oxa-dclohexane-1,1-dicarboxylato-2-methyl-1,4-butanediamine-platinum] (Compound 16)

The procedure described in Example 15 was followed except that 632 mg of 4-oxadclohexane-1,1-dicarboxylic acid was used instead of 523 mg dclobutane-1,1-dicarboxylic acid.

171 mg of the title compound 16 are obtained.

Found: C, 30.28; H, 4.88; N, 6.10 Found: C, 30.71; H, 4.72; N, 5.97; Pt, 41.56. Pt: 42.0%.

FAB-MS: (M + H) ⁺ = 469.

Example 17 Preparation of di- [(Dimethyl malonate) -2-methyl-1,4-butane-diamine-platinum] (Compound 17)

Example 15 was repeated except that 480 mg dimethylmalonic acid was used instead of 523 mg dclobutane-1,1-dicarboxylic acid.

141 mg of the title compound are obtained.

H, 4.72; N, 6.56; Pt, 45.65. Found: C, 27.80; H, 4.52; N, 6.26. Pt: 45.4%.

FAB-MS: (M + H) ⁺ = 427.

Example 18 Preparation of ds - [(Ethyl malonate) -2-methyl-1,4-butanediamine platinum] (Compound 18)

Example 15 was repeated except that 480 mg ethyl malonic acid was used instead of 523 mg dclobutane-1,1-dicarboxylic acid.

124 mg of the title compound are obtained.

Found: C, 27.60; H, 4.91; N, 6.10 Found: C, 28.11; H, 4.72; N, 6.56; Pt, 45.65. Pt: 45.2%.

FAB-MS: (M'H) U 427.

Example 19 Preparation of cis (Dichloro-2,2-dimethyl-1,4-butanediamine-platinum) (Compound 19)

The procedure of Example 1 was followed except that 2.80 g of 2,2-dimethyl-1,4-butanediamine was used instead of 2.12 g of 1,4-butanediamine. 11.2 g (82.3%) of di- [diiodo-2,2-dimethyl-1,4-butanediamine platinum] are obtained in the form of tan crystals. The procedure of Example 1 was followed, but using 1 g of the above compound, 589 mg of silver nitrate and 620 mg of sodium chloride.

283 mg of the title compound 19 are obtained in the form of yellow crystals.

Found: C, 19.12; H, 4.03; N, 7.01 Found: C, 18.86; H, 4.22; N, 7.33; Pt, 51.04. Pt: 50.8%.

FAB-MS: (M * H) ⁺ = 381.

Example 20 Preparation of ds- [Odato-2,2-dimethyl-1,4-butanediamine-platinum] (Compound 20)

The procedure described in Example 19 was followed except that a solution of 620 mg of sodium chloride in 5 ml of water was used. The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated to 5 mL and then cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

448 mg of the title compound 20 are obtained.

Found: C, 23.99; H, 4.11; N, 6.86. Found: C, 24.06; H, 4.04; N, 7.02; Pt, 48.85. Pt: 49.3%.

FAB-MS: (M + H) ⁺ = 399.

Example 21 Preparation of ds- [Malonato-2,2-dimethyl-1,4-butanediamine platinum] (Compound 21)

The procedure described in Example 20 was repeated except that a solution of potassium oxalate monohydrate (652 mg) in 5 ml of water was used instead of a solution of 368 mg of malonic acid in 6.90 ml of 1 N aqueous sodium hydroxide.

331 mg of the title compound 21 are obtained in the form of white crystals.

Found: C, 26.51; H, 4.55; N, 6.41. Found: C, 26.15; H, 4.39; N, 6.78; Pt, 47.20. Pt: 46.1%.

FAB MS: (M + H-413).

Example 22 Preparation of ds- [Cyclobutane-1,1-dicarboxylate-tert-dimethyl-1,4-butanediamine platinum] (Compound 22)

Proceed as in Example 20, except that a solution of 510 mg of cyclobutane-1,1-dicarboxylic acid in 6.90 ml of 1 N aqueous sodium hydroxide solution is replaced by a solution of 652 mg of potassium oxalate monohydrate in 5 ml of water. is used.

375 mg of the title compound are obtained in the form of white crystals.

Found: C, 31.81; H, 5.01; N, 6.36. Found: C, 31.79; H, 4.89; N, 6.18; Pt, 43.03. Pt: 43.2%.

FAB-MS: (M + H) ⁺ = 453.

Example 23 Preparation of ds- [4-Oxa-dclohexane-1,1-dicarboxyl-o-2,2-dimethyl-1,4-butanediamine-platinum] (Compound 23)

Example 20 was repeated except that 616 mg of 4-oxadclohexane-1,1-dicarboxylic acid was replaced by 6.90 ml of 1 N aqueous sodium hydroxide solution instead of a solution of 652 mg of potassium oxalate monohydrate in 5 ml of water. solution.

326 mg of the title compound 23 are obtained in the form of white crystals.

Found: C, 33.11; H, 4.97; N, 6.01 Found: C, 32.30; H, 5.00; N, 5.79; Pt, 40.35. Pt: 39.8%.

FAB MS: (M41)% 483.

Example 24 Preparation of di- [9-dimethyl malonate> 2,2-dimethyl-1,4-butanediamine-platinum] (Compound 24)

The procedure described in Example 20 was followed except that a solution of potassium oxalate monohydrate (652 mg) in 5 ml of water was used instead of 467 mg of dimethylmalonic acid in 6.90 ml of 1 N aqueous sodium hydroxide.

407 mg of the title compound 24 are obtained in the form of white crystals.

Found: C, 29.93; H, 5.02; N, 6.35; Pt: 44.20. C: 30.14, H: 5.28, N: 6.19, Pt: 43.9%.

FAB-MS (M + H) ⁺ = 441.

Example 25 Preparation of ds [dichloro-1,1-dimethyl-1,4-butanediamine platinum) (Compound 25)

The procedure described in Example 1 was followed except that 2.80 g of 1,1-dimethyl-1,4-butanediamine was used instead of 2.12 g of 1,4-butanediamine. 10.62 g (78.0%) of di- [diiodo-1,1-dimethyl-1,4-butanediamine platinum] are obtained in the form of reddish-brown crystals. The procedure of Example 1 was followed, but using 1 g of the above compound, 589 g of silver nitrate and 620 mg of sodium chloride.

264 mg of dm are obtained as yellow crystals.

Found: C, 18.77; H, 4.33; N, 7.58. Found: C, 18.77; H, 4.22; N, 7.33; Pt, 51.04. Pt: 50.7%.

FAB-MS (M + H) ⁺ = 381.

Example 26 Preparation of ds- [Oxalato-1,1-dimethyl-1,4-butanediamine platinum] (Compound 26)

The procedure described in Example 25 was followed except that 652 mg of potassium oxalate mono- instead of 620 mg of sodium chloride in 5 ml of water was used. solution of hydrate in 5 ml of water. After the addition of the above solution, the mixture was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated to 5 mL and then cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

433 g of dm 26 are obtained.

Found: C, 24.31; H, 4.22; N, 7.01 Found: C, 24.06; H, 4.04; N, 7.02; Pt, 48.85. Pt 49.2%.

FAB-MS. (M ⁺ H) ⁺ = 399.

Example 27 Preparation of ds [Cyclobutane-1,1-dicarboxylato-1,1-dimethyl-1,4-butanediamine platinum] (Compound 27)

The procedure described in Example 26 was followed except that a solution of 510 mg of cyclobutane-1,1-dicarboxylic acid in 6.90 ml of a 1N aqueous sodium hydroxide solution was substituted for 652 mg of potassium oxalate monohydrate in 5 ml of water. is used.

Compound 27 (207 mg, dm) was obtained as white crystals.

Found: C, 32.02; N, 5.11; N, 6.01 Found: C, 31.79; H, 4.89; N, 6.18; Pt, 43.03. Pt: 44.2%.

FAB-MS: (M ⁺ H) ⁺ -453.

Example 28 Preparation of dsi - [(Dimethyl malonate) -1,1-dimethyl-1,4-butanediamine platinum] (Compound 28)

Example 27 was repeated except that 467 mg dimethylmalonic acid was used instead of 510 mg of cyclobutane-1,1-dicarboxylic acid.

337 mg of dm are obtained in the form of white crystals.

Found: C: 30.22, H: 5.36, N: 6.10, Found: C: 29.93, H: 5.02, N: 6.35, Pt: 44.20. Pt: 43.4%.

FAB MS: (M + H) < ⁺ & gt ^; = 441.

Example 29 Preparation of ds [Dichloro-2-ethyl-1,4-butane-diamine-platinum] (Compound 29)

The procedure of Example 1 was followed except that 2.80 g of 2-ethyl-1,4-butanediamine was used instead of 2.12 g of 1,4-butanediamine. 10.32 g (75.8%) of cis [diiodo-2-ethyl-1,4-butanediamine platinum] are obtained in the form of reddish-brown crystals. The procedure of Example 1 was followed, but using 1 g of the above compound, 589 mg of silver nitrate and 620 mg of sodium chloride.

257 mg of the title compound 29 are obtained in the form of yellow crystals.

Found: C, 19.00; H, 4.35; N, 7.16 Found: C, 18.86; H, 4.22; N, 7.33; Pt, 51.04. Pt: 51.0%.

FAB-MS. (M + H) ⁺ = 381.

Example 30 Preparation of dsi [Oxalato-2-ethyl-1,4-butanediamine-platinum] (compound 30)

The procedure described in Example 29 was followed, except that a solution of 620 mg of sodium chloride in 5 ml of water was used instead of 652 mg of potassium oxalate monohydrate in 5 ml of water. The resulting solution was stirred at 60 ° C for 2 hours. The reaction mixture was concentrated to 5 mL and cooled to 0 ° C. The resulting white crystals were filtered off, washed with a little water at 0 ° C, then with ethanol and dried in vacuo.

428 mg of the title compound 30 are obtained.

Found: C, 24.33; H, 4.17; N, 6.96 Found: C, 24.06; H, 4.04; N, 7.02; Pt, 48.85. Pt: 48.5%.

FAB-MS: (M + 1)% 399.

Example 31 Preparation of ds [Malonato-2-ethyl-1,4-butanediamine-platinum] (Compound 31)

The procedure described in Example 30 was followed, except that a solution of potassium oxalate monohydrate (652 mg) in 5 ml of water was used instead of a solution of 368 mg of malonic acid in 6.90 ml of 1 N aqueous sodium hydroxide.

280 mg of the title compound are obtained.

Found: C, 26.53; H, 4.50; N, 6.59. Found: C, 26.15; H, 4.39; N, 6.78; Pt, 47.20. Pt: 46.1%.

FAB MS: (M + H) < + > = 413,

Example 32 Preparation of cis [Cyclobutane-1,1-dicarboxylato-2-ethyl-1,4-butanediamine platinum] (Compound 32)

Example 31 was repeated except that 510 mg dclobutane-1,1-dicarboxylic acid was used instead of 368 mg of malonic acid.

451 mg of the title compound 32 are obtained.

Found: C, 31.51; H, 4.67; N, 6.22. Found: C, 31.79; H, 4.89; N, 6.18; Pt, 43.03. Pt: 42.1%.

FAB-MS: (M * H)% 453.

Example 33 Preparation of Cis - [(Dimethyl malonate) -2-ethyl-1,4-butane diamine platinum] (Compound 33)

Example 31 was repeated except that 467 mg dimethyl malonic acid was used instead of 368 mg of malonic acid.

361 mg of the title compound 33 are obtained.

Found: C, 30.14; H, 5.18; N, 6.19. Found: C, 29.93; H, 5.02; N, 6.35; Pt, 44.20. Pt: 45.2%.

FAB-MS: (M + H) ⁺ = 441.

The physical properties of the compounds of the present invention are set forth in Table 1 below.

198,302

See Table 1 for physical constants of compounds of formula (1)

Compound number Solubility water (Mg / ml) Ν-Η IR absorption spectrum (cm (cm ^-1 ) C-O First > 2 * 3250-3150 Second > 5 3210-3130 1650-1610 Third . > io. 3230-3120 1670-1630 4th > 2 * 3240-3150 5th > 3 3220-3140 1700-1685 6th > 10 3260-3090 1640-1600 7th > 5 3220-3110 1660-1600 8th > 20 3230-3140 1640-1590 9th ^{> 1θ} * 3250-3110 1630-1590 10th > 2 * 3230-3120 11th > 3 3210-3100 1650-1600 12th > 5 3230-3090 1680-1620 13th > 2 * 3248-3225 14th > 50 3200-3125 1730-1610 15 > 8 3200-3125 1700-1620 16th > 15 3200-3130 1690-1610 17th > 20 3250-3255 1680-1640 18th > 10 * 3190-3120 1710-1620 19th > 2 * 3220-3130 20th > 3. 3260-3140 1690-1660 21 > 5 3190-3120 1680-1610 22nd > 3 3220-3130 1620-1600 23rd > 3 3230-3130 1650-1590 24th > 10 3250-3140 1640-1590 25th > 2 * 3210-3130 26th > 3 3220-3140 1700-1660 27th > 10 3220-3130 1640-1600 28th > ^1θ _Λ 3240-3140 1640-1590 29th > 2 * 3220-3130 30th > 3 3240-3120 1690-1660 31st > 10 3230-3130 1680-1600 32nd > 5 3220-3130 1530-1590 33rd > 10 3240-3150 1650-1600

* solubility in physiological saline

Given the solubility of ds-platln in saline of about 1.2 mg / ml, the compounds of the present invention are visibly more water soluble than cisplatin.

In addition, the compounds of the present invention are rapidly soluble in water. Therefore, the compounds of the invention, when administered as an injection, may be dissolved in water prior to administration and the resulting aqueous solution used immediately upon dissolution.

The antitumor activity of the compounds of the invention is demonstrated by the following experimental examples. 60

Experimental Example 1

Investigation of growth inhibitory activity on cultured L1210 mouse leukemia cells

L1210 mouse leukemia cells were cultured in RPMI medium containing 10% fetal calf serum.

Percent inhibition is calculated from the number of cells determined in the presence and absence of test compounds. LC Rf _J0 (i.e. koncentrádót causes 50% inhibition) are determined from graphs, which may be prepared by a logarithmic probability paper plotting the% inhibition of the function of conc t Me oh.

The results are shown in Table 2.

198 302

Table 2 Anti-Growth Activity of Compounds of Formula (I) in Cultured L1210 Mouse Leukemia Cell

Compound 1C _5O Number (pg / ml)

First

Second

Third

4th

5th

6th

7th

8. 9.

10th

11th

12th

13th

14th

15th

16th

17th

18th

19th

20. 21. 22.

23rd

24th

25th

26. 28.

29th

30th

31st

32nd

33rd

0.33

0.88

0.65

0.20

0.29

0.76

2.80

0.90

2.40

0.35

4.70

1.05

0.10

0.74

1.20

0.43

0.50

0.84

0.20

0.37

0.72

2.20

0.44

0.78

0.25

0.30

4,5Q

0.05

0.06

0.66

0.67

0.23

As can be seen from the results of Table 2, the compounds of this invention inhibit the growth of tumor cells at low concentrations.

The compounds of the present invention also exhibit excellent inhibition of the growth of tumor cells resistant to displatin, which results in 45 acquired resistance tendencies as a result of the administration of as-platinum. The above activity is described in Experimental Example 2 for compound 15 prepared according to the process of the invention.

Experimental Example 2 gg

Growth inhibition assay in cis-platinum-resistant tumor cells

In the abdominal cavity of female CDF _r mice, 1x10 L1210 mouse leukemia cells were inoculated. Two days after inoculation, 55 mice are treated intraperitoneally with 6 mg / kg ds-platinum, and after 5 days, tumor cells are inoculated into the abdominal cavity of another female CDF1 mouse, and the mice are treated in the same manner. By repeating the above procedure, tumor cells resistant to dsplatin are obtained. 60

Growth inhibitory activity against resistant tumor cells was assayed as described in the above method according to the first experimental example, and was determined against cis-platin resistant tumor cells 1C _N5 Rf (1C which R ₀ has _five designated hereinafter). Then, the ratio of R _{5 O} 1C against non-resistant tumor cells compared to _S 1C -értékéhez 0, i.e., the R _{5 O} 1C / 1C _S p ratio of cis-platin.

The results are shown in Table 3.

Table 3

Compound number 1C50R / 1C50 L1210 tumor P388 tumor Cis-Platin 11.4 10.7 15 3.19 3.26

It is evident from the results of Table 3 that the compounds of the present invention, even at low concentrations, inhibit the growth of tumor cells resistant to dsplatin.

Experimental Example 3

Examination of antitumor activity in vivo on L1210 mouse leukemia cell Female CDF seven weeks old, 1x10® L1210 mouse leukemia cell was inoculated into the abdominal cavity of mice. Starting day after the next day, the animals are treated with the test compound once daily for 5 days. Similarly to the control group (untreated group), only physiological saline was administered. The mean survival time (T) of the test compound treated group and the mean survival time (C) of the control group were determined and the% T / C value was calculated (T / Cx100) using the following equation.

JIQ. Mean survival time of treated group _x1 qq Mean survival time of control group

If the mouse is killed during the study due to the acute toxicity of the test compound, the 50% lethal dose (LD 50) is determined as usual.

The results are shown in Table 4. The max. (T / C) represents the maximum value of T / C and the optimum dose is the dose at which max (T / C) is reached, i.e. the amount that can be administered optimally,

Table 4: In vivo antitumor activity of compounds of formula (1)

Compound number Max (T / C) Optimal dose (mg / kg) LD ₅ o (mg / kg) First 203 2 4.8 Second 182 32 48.0 Third 132 8 8.4

-101

4th 225 2 2.4 · 5 273 4 6.0 6th 359 32 48.0 7th 176 64 - 8th 189 64 9th 222 64 96.0 10th 210 4 6.0 11th 139 64 12th 181 64 - 13th 187 2 4.2 14th 346 32 - 15th 182 32 80.0 16th 167 8 12.0 17th 238 32 - 18th 264 16 24.0 19th 359 4 6.0 20th 272 8 12.0 21st 301 32 48.0 22nd 320 128 23rd 159 32 - 24th 253 64 - 25th 150 2 3.0 29th 261 2 3.0 30th 253 8 - 32nd 275 32 -

From the above results, it can be seen that the compounds of the present invention have a life-prolonging effect in mice inoculated with L1210 murine leukemia cells,

The compounds of the present invention also exhibit a life-prolonging effect in mice inoculated with other tumor cells other than L1210 mouse leukemia cells, as demonstrated in Experiment 4 for Compound 15.

Experimental Example 4.

Testing for antitumor activity in vivo on various tumors, 1x10 * mouse leukemia P388 cells in 7-week-old female CDFi mice were inoculated and Compounds 15 was administered intraperitoneally once daily for 5 days starting the next day.

Lewis cell tüdőkardnoma another experiment, the abdominal cavities of male BDF mice causing lxlO ⁶ mice inoculated with lung cancer, and from the next day for 5 days, the animals were daily treated intraperitoneally with Compound 15 once.

In a third experiment, 1x10 * mouse fibrosarcoma m5076 cells were subcutaneously injected into the side of female C57BL / 6 mice, and the animals were treated with Compound 15 intraperitoneally from the following day.

In a fourth experiment, 1x10 * mouse colon cancer (colon 26) cells were inoculated into the peritoneal cavity of female CDFi mice, and the animals were treated with Compound 15 intraperitoneally from the following day. Physiological saline was added to the appropriate control groups (untreated group).

From the survival time of the test compound treated group and the control group, the mean survival times are calculated. From these values, calculate

T / C% based on the following equation:

Mean survival time T / C = R B group ^eze _χ jqq

Mean survival time of the control group The results are shown in Table 5.

Table 5

Compound 15 has antitumor activity on various tumors

tumor max (T / C) optimum dose (Mg / kg) P388 260 32 LL 222 32 M5076 152 16 colon 26 198 32

The results of Table 5 show that the compounds of the present invention also have a prolonged life span in mice infected with various tumor cells.

Renal toxicity of the compounds of the present invention is described in Experimental Example 5.

Experimental Example 5 Renal toxicity of compounds of formula (I)

The test compound is administered once to 6-week-old male CDF1 mice intraperitoneally. After four days, the animals are bled to determine the blood urea nitrogen concentration (BUN value).

The results are shown in Table 6. The optimum dose of dsplatin in Experiment 3 is 4 mg / kg, but in the above kidney toxicity assay, the BUN value is much higher than the normal value (30 mg / dL or less), when dispatin is administered in an amount corresponding to four times the optimum dose. Based on the above result, the compounds of the present invention are also used in amounts equal to or greater than four times the optimal dosage as determined in Experiment 3. In Table 6, the body weight ratio is the quotient of the body weight measured on the day after the compound was administered and on the 4th day thereafter.

Compound number Dose (Mg / kg) Weight gold BUN value (Mg / dl) physiological saline - 1.05 22.7 Cis-Platin 16 0.72 92.9 First 8 0.72 92.9 Second 128 0.73 16.2 4th 8 0.75 28.4 5th 16 0.76 12.9 6th 128 0.75 24.6

-111

7th 256 0.85 13.1 8. · 256 0.71 25.4 10th 16 0.74 21.3 11th 256 1.09 23.2 12th 256 0.94 16.8 13th 20 0.74 22.6 14th 128 0.72 15.9 15th 240 0.74 19.8 17th 128 0.73 16.7 18th 64 0,7.4 19.6 19th 16 0.76 15.7 20th 32 0.75 13.5 21st 128 0.76 16.7 22nd 512 0.89 14.4 23rd 128. 0.79 15.0 24th 256 0.79 19.7 25th 8 0.79 16.8 29th 8 0.72 18.1 30th 32 0.87 18.2 32nd 128 0.74 19.7

Table 6 shows that the BON value after administration of the compounds of the present invention is much lower than that obtained with commercially available cisplatin and is approximately the same as the BUN value after physiological saline. The above results indicate that the compounds of the present invention have very low renal toxicity. As a result, the compounds of the present invention are useful as antitumor agents with very low renal toxicity. Due to the above characteristics and their high solubility in water, the compounds of the present invention can be administered by the intravenous injection in large doses, not continuously.

The compounds of the present invention may also contain diamines containing asymmetric carbon atoms as ligands. The above amines are subjected to optical resolution to produce optical isomers. Using the isomers as ligands, the corresponding complexes are prepared and their biological activity is assayed. The above procedures and assays are illustrated by the following Examples and Experimental Examples for Compound 15.

Example 34

Preparation of R-2-Methyl-1,4-butanediamine

To a mixture of 200 g of concentrated sulfuric acid and 320 ml of benzene is added 40 g of R-3-methyladaptic acid. The mixture was dissolved in 3-methyladipic acid by heating in a water bath at 45 ° C. To the resulting solution was added 56 g of sodium azide in portions and the mixture was kept at 45-50 ° C. After the addition of sodium azide, the mixture was stirred for 10 minutes. A saturated solution of sodium hydroxide (200 g) was added dropwise to the reaction mixture. The resulting sodium sulfate precipitate was removed by filtration and the benzene phase was separated from the filtrate. The aqueous phase of the filtrate was extracted with 500 ml of benzene, 500 ml of diethyl ether and finally 500 ml of chloroform four times. All extracts were combined and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated on a rotary evaporator. The concentrate was evaporated in vacuo to give dm.

Yield: 6.92 g (27.1%)

Boiling point: 83 ° C / 387 ° Pa

Purity: 93.3%

Optical purity: 100%

In the above example and in the other examples, purity and optical purity are determined by known methods, such as gas chromatography, optical rotation, or the like. "

Example 35

Separation of Optical Isomers of 2-Methyl-1,4-Butanediamine by Optical Resolution

For optical resolution of 2-methyl-1,4-butanediamine, the above compound is converted to the salt with dibenzoyl tartaric acid and recrystallized (the optical isomers have different solubilities). For the preparation of R-2-methyl-1,4-butanediamine, (-) - dibenzoyl tartaric acid and for S-2-methyl-1,4-butanediamine, (+) - dibenzoyl tartaric acid is used. The yield of resolution and the purity and optical purity of the two isomers of 2-methyl-1,4-butanediamine are shown in Table 7.

Table 7

Resolution of 2-methyl-1,4-butanediamine

Resolution Yield (%) Purity (%) Optical Purity (%) R isomer 57.8 100 98.6 S-isomer 51.4 100 98.8

Using the isomers prepared in Examples 34 and 35, as-[dclobutane-1,1-dicarboxylato-R-2-methyl-1,4-butanediamine platinum] was prepared as in Example 15. t (compound 15R) and di- [cyclobutane-1,1-dicarboxylato-S-2-methyl-1,4-butanediamine platinum (compound 15S). Table 8 shows the yields and elemental analysis results of the above complexes when synthesized starting from potassium tetrachloroplatinate, the physical constants are shown in Table 9. The (M ⁺ H) ⁺ value of the complexes measured by the FAB-MS method was 439 in both cases.

Table 8

Compound number Yield (%) Elemental Analysis Results (%) C Η N Pt 15R 24.6 29.98 4.43 6.22 44.8 15S 23.1 30.21 4.37 6.36 45.0

-121

Table 9

Compound number Solubility in water (mg / ml) IR absorption spectrum (cm ' ¹ ) N-H C = O 15R 15 3200-3125 1700-1620 15S 15 3210-3130 1700-1620

The optical isomers of 15R and 15S were tested as described in Experimental Examples 1 and 3. The results are shown in Table 10.

Table 10

Compound number IC50 (/ Rg / ml) Max (T / C) Optimal LD _{5 0} dose (1 (mg / kg) ng / ml) 15R 0.78 189 32 33.6 15S 1.08 206 32 48.0 The optical isomers 15R and 15S are shown in Experimental Example 4.

We also investigate. The results are shown in Table 11.

Table 11.

Compound number tumor max (T / C) optimum dose . (Mg / kg) 15R P388 253 20 15R LL 166 30 15S P238 253 40 15S LL 164 50

The renal toxicity of the 15R and 15S isomers was also determined as described in Experiment 5. The results are shown in Table 12. Compounds were administered in an amount equivalent to four times the optimal dosages shown in Table 10.

Table 12

Compound Dose Weight A wedge for sin number (Mg / kg) gold (Mg / dl) 15R 128 0.71 10.6 15S 128 0.90 21.4

According to the above results, 15R and 15S are highly soluble in water, exhibit excellent antitumor activity on a variety of tumor cells and have very low renal toxicity.

Example 36

Preparation of Compound 5

The procedure described in Example 4 was followed except that a solution of 346 mg of oxalic acid dihydrate in 5 ml of water was used instead of 636 mg of sodium chloride in 5 ml of water. The resulting solution was stirred at 40 ° C for 24 hours. The reaction mixture was concentrated to 5 mL and then cooled to 0 ° C. The resulting white crystals were filtered off and washed with a little water at 0 ° C and then with ethanol. The compound obtained is the same as that obtained in Example 5 according to the analytical results.

Example 37

Preparation of Compound 4

The procedure described in Example 4 was followed except that a solution of 560 mg of silver sulfate in 150 ml of water was used instead of a solution of 604 mg of silver nitrate in 10 ml of water. The resulting solution was stirred at 80 ° C for 20 minutes. In the same manner as in Example 4, compound 4 was obtained in the form of yellow crystals. The results of compound analysis were identical to those of compound 4 prepared according to Example 4.

The compounds of the present invention inhibit the growth of tumor cells at very low concentrations and thus exhibit excellent antitumor activity against various tumor cells. The compounds of the present invention are highly water soluble and rapidly soluble in water. They have a low renal toxicity and vomiting effect. In addition, the compounds of the present invention have low bone marrow toxicity as opposed to the known anti-tumor agents of the known platinum complex, in particular white blood cell counts and their anti-platelet toxicity. In addition, the restoration to normal conditions is very fast and thus easy to control using the compounds of the present invention as an antitumor agent. Due to the above properties, the compounds of the present invention are excellent antitumor agents. In addition, they have the advantage of being stable at room temperature and air, so they do not have to be stored at low temperatures.

Claims (24)

PATENT CLAIMS A process for the preparation of diamine-platinum (H) complexes of formula (II): Ri, _{R2, R3} and R4 is hydrogen or lower alkyl, the two X's is a halogen atom or, together with formula (a) or the formula (b) the group - the latter, wherein R _s and R "is hydrogen or lower alkyl -, or a group of formula (c) or (d), wherein m is 1 or 2, wherein a diamine of formula (V) wherein R ₂ , R ₂ , R ₃ and R 4 is reacting a tetrahaloplatinate of formula (IV) wherein M is a monovalent cation atom and Hal is a halogen atom as defined in the foregoing, and the resulting dihalodiamine-platinum complex of formula (Ha) is R ₁ , R ₂ , R ₃ , R 4 and Hal are as defined above - optionally reacted with silver ions in the presence of water and the resulting diaco complex is y (Via), With dicarboxylic acid of the formula -131 (Vb), (Vle) or Vld, wherein R ₅ , R 6 and m are as defined in the disclosure, or a salt thereof. (Priority: July 1, 1986) Process for the preparation of a compound of formula (11) according to claim 1, wherein R 1 and R ₂ are hydrogen and R ₃ , R 4 and X are as defined in claim 1, characterized in that the starting material is (V). A compound of formula wherein R ₁ and R ₂ are as defined in the preamble and R ₃ and R 1 are as defined in claim 1. (Priority: July 1, 1986) A process for the preparation of a compound of formula (11) according to claim 1 wherein two X are linked together to form (b) wherein R 1 and R 4 are hydrogen or lower alkyl or (c) characterized in that the diacvo complex is reacted with a lower alkyl group with a mono-or disubstituted malonic acid or dclobutane-1,1-dicarboxylic acid. (Priority: 07.07.1986) 4. The process according to any one of claims 1 to 5, wherein the diamine of the formula V is 0.5 to 4 mol per mole of the compound of the formula IV, the silver ions 0.5 to 6 equivalents per dihydrogenodiamine-platinum complex per 1 equiv. , and the dicarboxylic acid or its salt is used in an amount of 0.5 to 10 moles per 1 mole of diacvo complex. (Priority: 07.07.1986) 5. A process according to any one of claims 1 to 3, wherein the compound of formula IV is used wherein M is sodium, potassium or cesium and Hal is chlorine, bromine or iodine. (Priority: 07.07.1986) The process according to claim 2 or 3, wherein the diamine of formula (V) is 1,4-butanediamine, 2-methyl-1,4-butanediamine or 2-ethyl-1,4 butane diamine. (Priority: July 1, 1986) 7. A process according to claim 3 for the preparation of di- [dclobutane-1,1-dicarboxylato-1,4-butanediamine platinum], wherein the diamine of formula V is 1,4-butanediamine and the dicarboxylic acid is dclobutane-1,1-dicarboxylic acid is used. (Priority: 12/12/1986) A process for the preparation of di- [malonate-2-methyl-1,4-butanediamine-platinum] according to claim 3, wherein the diamine of formula (V) is 2-methyl-1,4-butanediamine. , the dicarboxylic acid used is malonic acid. (Priority: August 27, 1985) 9. A process for the preparation of cis [dclobutane-1,1-dicarboxylato-2-methyl-1,4-butanediamine-platinum] according to claim 3, wherein the diamine of formula (V) is 2-methyl-1. 4-butanediamine and diclobutane-1,1-dicarboxylic acid as the dicarboxylic acid. (Priority: Aug 27, 1985) The process for the preparation of di- [dimethyl malonate-2-methyl-1,4-butanediamine-platinum] according to claim 3, wherein the diamine of formula (V) is 2-methyl-1,4-butane. -diamine and dimethyl malonic acid as the dicarboxylic acid. (Priority: August 27, 1985) The process for the preparation of di- [ethyl malonate-2-methyl-1,4-butanediamine-platinum] according to claim 3, wherein the diamine of formula (V) is 2-methyl-1,4-butane. diamine, and ethyl malonic acid is used as the dicarboxylic acid. (Priority: Aug 27, 1985) 12. A process for the preparation of di- [malonate-2-ethyl-1,4-butanediamine-platinum] according to claim 3, wherein the diamine of formula (V) is 2-ethyl-1,4-butanediamine. and the dicarboxylic acid is malonic acid. (Priority: July 1, 1986) 13. A process according to claim 3 for the preparation of di- [dclobutane-1,1-dicarboxylato-2-ethyl-1,4-butanediamine-platinum] wherein the diamine of formula (V) is 2-ethyl-1. 4-butanediamine, diclobutane-1,1-dicarboxylic acid is used as the dicarboxylic acid. (Priority: July 1, 1986) The process for the preparation of di- [dimethyl malonate-2-ethyl-1,4-butanediamine-platinum] according to claim 3, wherein the diamine of formula (V) is 2-ethyl-1,4-butane. dimethyl malonic acid is used as the dicarboxylic acid. (Priority. July 1, 1986) 15. A process according to claim 3 for the preparation of di- [dclobutane-1,1-dicarboxylato-R-2-methyl-1,4-butanediamine platinum] wherein the diamine of formula (V) is R-2. methyl-1,4-butanediamine and diclobutane-1,1-dicarboxylic acid as the dicarboxylic acid. (Priority. April 25, 1986) 16. A process according to claim 3 for the preparation of di- [dclobutane-1,1-dicarboxylato-S-2-methyl-1,4-butanediamine-platinum] wherein the diamine of formula (V) is S-2. methyl-1,4-butanediamine, diclobutane-1,1-dicarboxylic acid is used as the dicarboxylic acid. (Priority: 07.07.1986) 17. A process according to claim 1 for the preparation of compounds of formula 11 wherein R 1 is hydrogen or lower alkyl, R ₂ is hydrogen and R ₃ and R 1 are hydrogen or R 1 and R ₂ are hydrogen and R ₃ and R4 is methyl, and the two X are as defined in claim 1, wherein the appropriate starting compounds are used. (Priority: February 12, 1986) 18. A process according to claim 1 for the preparation of compounds of formula (U) wherein R ₁ and R ₂ are hydrogen, one of R ₃ and R ₄ is hydrogen, the other is methyl, and the two X are halogen, or together formula (c) or (b) or (d) to form a group of formula wherein _R5, R and m are as defined in claim 1, wherein the character cooked to using the appropriate starting materials. -141 198,302 (Priority: Aug 27, 1985) A process according to claim 1 for the preparation of compounds of formula 11 wherein R 1, R ₂ , R ₃ , R 4 are as defined in claim 1 and the two X are chlorine atoms, wherein the corresponding starting materials are compounds are used. (Priority: July 1, 1986) A process according to claim 1 for the preparation of compounds of formula II wherein R 1, R 1, R ₃ , R 4 are as defined in claim 1 and the two X are groups of formula (a), wherein starting compounds. (Priority: July 1, 1986) A process for the preparation of a compound of formula (II) according to claim 1 wherein R 1, R 1, R ₃ , R 4 are as defined in claim 1 and the two X are of formula (d) wherein m is 1 or 2, characterized in that the appropriate starting compounds are used. (Priority: July 1, 1986) 22. A process for the preparation of a pharmaceutical composition comprising the steps of: 1. A process for the preparation of a compound of formula (II) according to claim 1, wherein R ₁ , R ₁ , R ₃ , R 4 and X is as defined in claim 1, when mixed with excipients and / or other excipients commonly used in the preparation of pharmaceuticals to form a pharmaceutical composition. (Priority: 01.07.1986) _n 23. A process for the preparation of a pharmaceutical composition, wherein the compound of formula (11) according to claim 18, wherein R ₁ , R ₂ , R ₃ , R 4 and X are as defined in claim 18, is a compound of formula (11). mixed with excipients and / or other excipients commonly used in pharmaceutical formulations to form a pharmaceutical composition. (Priority: Aug 27, 1985) 24. A process for the preparation of a pharmaceutical composition, wherein a compound of the general formula (11) according to claim 17, wherein R 1, R _a , R ₃ , R 4 and X are as defined in claim 17, is present in a pharmaceutical composition. mixed with conventional carriers and / or other excipients to form a pharmaceutical composition.